Characterization of tumor microbiome and associations with prognosis in intrahepatic cholangiocarcinoma.

BACKGROUND: The tumor microbiome has been characterized in several malignancies; however, no previous studies have investigated its role in intrahepatic cholangiocarcinoma (ICC). Hence, we explored the tumor microbiome and its association with prognosis in ICC. METHODS: One hundred and twenty-one ICC tumor samples and 89 adjacent normal tissues were profiled by 16S rRNA sequencing. Microbial differences between tumor and adjacent nontumoral liver tissues were assessed. Tumor microbial composition was then evaluated to detect its association with prognosis. Finally, a risk score calculated by the tumor microbiota was accessed by the least absolute shrinkage and selector operator method (Lasso) to predict prognosis of ICC. RESULTS: The tumor microbiome displayed a greater diversity than that in adjacent nontumoral liver tissues. Tumor samples were characterized by a higher abundance of Firmicutes, Actinobacteria, Bacteroidetes, and Acidobacteriota. Higher tumor microbial α diversity was associated with lymph node metastasis and predicted shortened overall survival (OS) and recurrence-free survival (RFS). A total of 11 bacteria were selected to generate the risk score by Lasso. This score showed potential in predicting OS, and was an independent risk factor for OS. CONCLUSION: In conclusion, our study characterized the tumor microbiome and revealed its role in predicting prognosis in ICC.

Association of BRAF Variants With Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma.

Importance: BRAF variants are associated with tumor progression; however, the prevalence of BRAF variant subtypes and their association with disease characteristics, prognosis, and targeted therapy response in patients with intrahepatic cholangiocarcinoma (ICC) are largely unknown. Objective: To explore the association of BRAF variant subtypes with disease characteristics, prognosis, and targeted therapy response in patients with ICC. Design, Setting, and Participants: In this cohort study, 1175 patients who underwent curative resection for ICC from January 1, 2009, through December 31, 2017, were evaluated at a single hospital in China. Whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify BRAF variants. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using Cox proportional hazards regression. Associations between BRAF variants and targeted therapy response were tested in 6 BRAF-variant, patient-derived organoid lines and in 3 of the patient donors of those lines. Data were analyzed from June 1, 2021, to March 15, 2022. Interventions: Hepatectomy in patients with ICC. Main Outcomes and Measures: The association of BRAF variant subtypes with OS and DFS. Results: Of 1175 patients with ICC, the mean (SD) age was 59.4 (10.4) years and 701 (59.7%) were men. A total of 20 different subtypes of BRAF somatic variance affecting 49 patients (4.2%) were identified; V600E was the most frequent allele in this cohort, accounting for 27% of the identified BRAF variants, followed by K601E (14%), D594G (12%), and N581S (6%). Compared with patients with non-V600E BRAF variants, patients with BRAF V600E variants were more likely to have large tumor size (10 of 13 [77%] vs 12 of 36 [33%]; P = .007), multiple tumors (7 of 13 [54%] vs 8 of 36 [22%]; P = .04), and more vascular/bile duct invasion (7 of 13 [54%] vs 8 of 36 [22%]; P = .04). Multivariate analysis revealed that BRAF V600E variants, but not overall BRAF variants or non-V600E BRAF variants, were associated with poor OS (hazard ratio [HR], 1.87; 95% CI, 1.05-3.33; P = .03) and DFS (HR, 1.66; 95% CI, 1.03-2.97; P = .04). There were also broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. Conclusions and Relevance: The findings of this cohort study suggest that there are broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. Identifying and classifying BRAF variants may be able to help guide precise treatment for patients with ICC.

Efficacy and Safety of Aspirin for Prevention of Hepatocellular Carcinoma: An Updated Meta-analysis.

Background and Aims: Previous meta-analyses have shown that aspirin use may reduce the risk of hepatocellular carcinoma (HCC). However, the optimal dose, frequency, and duration of aspirin use or the safety and efficacy of aspirin in target populations for HCC prevention remain unclear. The study aim was to investigate the efficacy and safety of aspirin for prevention of HCC. Methods: Publications were retrieved by a comprehensive literature research of several databases. Based on a random-effects model, hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. The dose-response relationship between aspirin use and HCC risk was assessed with a restricted cubic spline model. Results: Twenty-two studies were included in the meta-analysis. Aspirin use was associated with a reduced risk of HCC (HR=0.64, 95% CI: 0.56-0.75). The effect was robust across sex and age; however, women and the non-elderly had the greatest benefit from aspirin use. The preventive effect was well reproduced in those with comorbidities. Daily use and long-term use of aspirin appeared to offer greater benefits. Aspirin 100 mg/d was associated with maximum reduction of HCC risk. Aspirin use did slightly increase the risk of bleeding (HR=1.14, 95% CI: 1.02-1.27). Conclusions: Our meta-analysis confirmed that use of aspirin significantly reduced the incident risk of HCC. Regular and long-term aspirin use offers a greater advantage. Aspirin use was associated with an increased risk of bleeding. We recommend 100 mg/d aspirin as a feasible dose for further research on primary prevention of HCC in a broad at-risk population.

Advances and trends in microbial production of polyhydroxyalkanoates and their building blocks.

With the rapid development of synthetic biology, a variety of biopolymers can be obtained by recombinant microorganisms. Polyhydroxyalkanoates (PHA) is one of the most popular one with promising material properties, such as biodegradability and biocompatibility against the petrol-based plastics. This study reviews the recent studies focusing on the microbial synthesis of PHA, including chassis engineering, pathways engineering for various substrates utilization and PHA monomer synthesis, and PHA synthase modification. In particular, advances in metabolic engineering of dominant workhorses, for example Halomonas, Ralstonia eutropha, Escherichia coli and Pseudomonas, with outstanding PHA accumulation capability, were summarized and discussed, providing a full landscape of diverse PHA biosynthesis. Meanwhile, we also introduced the recent efforts focusing on structural analysis and mutagenesis of PHA synthase, which significantly determines the polymerization activity of varied monomer structures and PHA molecular weight. Besides, perspectives and solutions were thus proposed for achieving scale-up PHA of low cost with customized material property in the coming future.

Sex and regional disparities in incidence of hepatocellular carcinoma in autoimmune hepatitis: a systematic review and meta-analysis.

BACKGROUND: Recent studies have identified an increased risk of hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH). Sex and regional disparities in incidence of HCC in AIH continue to be reported worldwide. Nevertheless, the magnitude of this gap remains unknown. METHOD: We searched several databases including PubMed, Embase, Web of Science, Cochrane Library, Wanfang Data, CNKI and SinoMed. Incidence rates of HCC in AIH were combined and analyzed following the EBayes method. Incidence rate ratios were pooled to assess the sex differences. The impact of population difference, sex, age, cirrhotic condition was further analyzed with subgroup analysis and linear regression analysis. RESULT: 39 studies meeting our eligibility criteria were chosen for the analysis. The pooled incidence rate of HCC in AIH was 3.54 per 1000 person years (95% CI 2.76-4.55). Pooled IRR for the risk of HCC in male AIH patients compared to female was 2.16 (95% CI 1.25-3.75), with mild heterogeneity among studies. The pooled HCC incidence rate in AIH by continents was as follows: Europe 2.37 per 1000 person-years (95% CI 1.45-3.88), Asia 6.18 per 1000 person-years (95%CI 5.51-6.93), North America 2.97 per 1000 person-years (95%CI 2.40-3.68), Oceania 2.60 (95%CI 0.54-7.58). The pooled HCC incidence rate in AIH-related cirrhosis by continent was as follows: Europe 6.35 per 1000 person-years (95%CI 3.94-10.22), Asia 17.02 per 1000 person-years (95%CI 11.18-25.91), North America 10.89 per 1000 person-years (95%CI 6.69-17.74). CONCLUSION: A higher HCC incidence in AIH was observed among male and in Asian populations. Cirrhosis status at AIH diagnosis is significantly associated with an increased incidence rate for HCC, and routine HCC surveillance is recommended for patients with AIH cirrhosis, especially for those in Asia.

RECK expression is associated with angiogenesis and immunogenic Tumor Microenvironment in Hepatocellular Carcinoma, and is a prognostic factor for better survival.

Angiogenesis and immunosuppression have been described as closely related processes that can occur in parallel. As an inhibitor of matrix metalloproteinase, whether the level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in hepatocellular carcinoma (HCC) reflects a link between angiogenesis and immunosuppression is still unknown. We analyzed RNA expression, immune infiltration and survival of HCC from The Cancer Genome Atlas databases. Immune scores and stromal scores were calculated based on the ESTIMATE algorithm to quantify the immune and stromal components in HCC. The association between RECK and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high RECK expression was significantly better than that of patients with low RECK expression. High RECK expression was associated with high ESTIMATE Score, recruitment of more tumor-infiltrating lymphocytes, low tumor purity, and high PD-L1 expression. In addition, positive RECK expression was associated with a lower incidence of vascular invasion and recurrence, a lower level of alpha fetoprotein (AFP) and microvessel density and a better tumor differentiation. Multivariate analyses revealed that reduced RECK expression was an independent prognostic factor for recurrence and poor prognosis. In conclusion, high RECK expression reflects an immunogenic and hypovascularity status in HCC. RECK is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive anti-angiogenic therapy or immunotherapy.

Clinical Benefit of Antiviral Agents for Hepatocellular Carcinoma Patients With Low Preoperative HBV-DNA Loads Undergoing Curative Resection: A Meta-Analysis.

BACKGROUND AND AIMS: The clinical benefit of adjuvant antiviral therapy after curative therapy for HCC in patients with high preoperative HBV-DNA loads has been studied widely but that in patients with low preoperative HBV-DNA loads remains controversial. The purpose of this study was to determine the effect of antiviral treatment prophylaxis on HBV reactivation, overall survival (OS), and postoperative liver function in patients with low preoperative HBV-DNA levels undergoing curative resection. METHODS: A meta-analysis was conducted by searching Web of Science, PubMed, Embase, and Cochrane Library until May 2020. We used REVMAN for data analysis and completed the study under the PRISMA guidelines. RESULTS: Three randomized trials and seven cohort studies, comprising of 1,131 individuals, were included in the meta-analysis. Antiviral treatment significantly reduced the rate of HBV reactivation after curative treatment of HCC, with a pooled risk ratio of 0.12 (95% c.i. 0.07 to 0.21; P < 0.00001). The trials were consistently favorable for the antiviral group, with a pooled hazard ratio of 0.52 (95% c.i. 0.37 to 0.74; P = 0.0002) in respect of OS rate. However, by pooling the data from studies that reported ALT on the 30th day postoperatively, the result didn't reach statistical significance (mean difference -4.38, 95% c.i. -13.83 to 5.07; P = 0.36). The I² values of the heterogeneity test for the above three comparisons are zero. CONCLUSION: Antiviral therapy during curative resection is effective in reducing HBV reactivation and improving OS rate in HCC patients with low viral load.

Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: A systematic review with meta-analysis.

BACKGROUND AND AIM: The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS: A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS: Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION: Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.

Can the Novel LumboIliac Triangle Technique Based on Biplane Oblique Fluoroscopy Facilitate Transforaminal Percutaneous Endoscopic Lumbar Discectomy for Patients with L5-S1 Disc Herniation Combined with High Iliac Crest? Case-Control Study of 100 Patients.

BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) via the transforaminal approach is difficult at L5-S1 in patients presenting with high iliac crests (HIC). The conventional wisdom is that measurement using lumbar radiography, computed tomography (CT), or magnetic resonance imaging (MRI) is necessary. OBJECTIVES: The objective of this study was to introduce a lumbo-iliac triangular (LI-Tri) technique based on biplane oblique fluoroscopy and verify whether it facilitated transforaminal PELD for patients with L5-S1 lumbar disc herniation (LDH) combined with HIC. STUDY DESIGN: A retrospective analysis. SETTING: All data were from Honghui Hospital in Xi'an. METHODS: One hundred patients with L5-S1 LDH combined with HIC were treated with PELD. The LI-Tri technique was used in the first 50 patients (applied group). The other 50 patients were classified as the nonapplied group, in which the conventional technique was performed. Clinical outcome evaluation included Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) scores. The intervals of follow-up were scheduled at 1 day and 1, 3, 6, 12, and 24 months postoperatively. RESULTS: No significant difference was observed with respect to demographic information (P < .05, respectively). There were 8 patients in the nonapplied group with difficult punctures. Together with the remaining 50 patients, the puncture was successful with the LI-Tri technique. The mean operative duration was shorter in the applied group (55 vs 70 min, P < .01). Compared to the preoperative data, only the back pain VAS and ODI in the nonapplied group were nonsignificantly lower at one day postoperatively (P > .05, respectively). With the exception of the back pain VAS and ODI at one day postoperatively, no significant differences were observed in the 3 parameters at other time points postoperatively between 2 groups (P > .05, respectively). LIMITATIONS: The study is limited by its retrospective, nonrandomized controlled design. CONCLUSIONS: For patients with L5-S1 LDH combined with HIC treated by transforaminal PELD, the LI-Tri technique is simple and effective in preoperative evaluations, locating the skin entry point and guiding the puncture trajectory. Compared to the conventional technique, it shows advantages in terms of reducing intraoperative surgical duration and promoting fast postoperative recovery. KEY WORDS: Endoscopic discectomy, iliac crest, L5-S1 disc, PELD, percutaneous, transforaminal.

Cocktail Treatment with a Gelatin Sponge Impregnated with Ropivacaine, Dexamethasone, and Vitamin B12 Promotes Early Postoperative Recovery after Percutaneous Endoscopic Lumbar Discectomy: A Retrospective, Case-Controlled Study.

BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) can only relieve mechanical compression but cannot directly reduce the inflammatory reaction of the adjacent nerve root, which contributes to persistent pain and physical disabilities postoperatively. Numerous studies have explored the application of epidural steroids after an open lumbar discectomy in relieving pain by reducing local inflammatory reactions and further peridural scar formation. OBJECTIVES: To explore that whether "cocktail treatment" in which a gelatin sponge was impregnated with ropivacaine, dexamethasone, and vitamin B12 promoted early postoperative recovery after PELD. STUDY DESIGN: Retrospective, case-controlled study. SETTING: All data were from Hong-Hui Hospital in Xi'an. METHODS: Between January 2016 and January 2017, 100 patients of single-level lumbar disc herniation were treated with PELD in our hospitals. The cocktail treatment was applied in the first 50 patients (group cocktail), and an equal size gelatin sponge without drugs was used in the other 50 patients as control (group noncocktail). The clinical outcome evaluation included the Visual Analog Scale (VAS) score for back and leg pain and Oswestry Disability Index (ODI) score. RESULTS: There was a significant difference in the mean periods of return to work (4.25 ± 1.88 weeks in the cocktail group and 5.18 ± 2.19 weeks in the noncocktail group) (P < 0.01). Compared with the preoperative data, a significant improvement in VAS scores of back pain and sciatica and ODI were observed in each follow-up interval (P < 0.05, respectively). In the noncocktail group, there were visible fluctuations in the 3 indicators within the first week after surgery. This phenomenon was not observed in the cocktail group, a difference that was statistically significant (P < 0.05, respectively). In further follow-up, no significant differences were observed between the 2 groups (P > 0.05, respectively). LIMITATIONS: The nonrandomized, single-center, retrospective design is a major limitation of this study. CONCLUSIONS: The "cocktail treatment" with a gelatin sponge impregnated with ropivacaine, dexamethasone, and vitamin B12 promotes early and satisfactory back and leg pain relief and fast functional recovery after PELD. KEY WORDS: Endoscopic lumbar discectomy, lumbar disc herniation, steroids, nerve root block, gelatin sponge.

Correction to: Hepatic metastatic paraganglioma 12 years after retroperitoneal paraganglioma resection: a case report.

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Hepatic metastatic paraganglioma 12 years after retroperitoneal paraganglioma resection: a case report.

BACKGROUND: Paragangliomas, also known as chemodectomas, are rare tumors arise from chemoreceptor tissue, and most commonly locate at the bifurcation of the common carotid, the jugular foramen, aortic arch, and retroperitoneum. Paragangliomas generally are considered to be benign tumors, and rarely produce local or distant metastases. Metastasis to liver is extremely rare. CASE PRESENTATION: We report the case of a 39-year-old woman, who had undergone resection of a retroperitoneal paraganglioma at her local hospital for 12 years. She was referred to our hospital for further evaluation of a hepatic mass, which was misdignosed as hepatocellular carcinoma (HCC) and was treated by transarterial chemoembolization (TACE) in the local hospital 6 years ago. At admission, CT scan revealed a huge hypervascular mass with many feeding arteries, almost the same size as 5 years ago. Ultrasound-guided biopsy of the liver tumor was performed and immunohistochemical examination confirmed the diagnosis of hepatic metastatic paraganglioma. Though liver metastasis failed to achieve complete response or partial response to TACE treatment, it remained stable without progression during the 7-year follow-up. CONCLUSION: Paragangliomas are slow growing tumors and metastasis may develop decades after resection of the primary lesion. Long-term follow-up is necessary, and curative or palliative treatment should be considered to control symptoms, improve life quality, reduce complications and prolong survival.

The effect of non-structural components and lignin on hemicellulose extraction.

As the important structural component of corn stover, hemicellulose could be converted into a variety of high value-added products. However, high quality hemicellulose extraction is not an easy issue. The present study aims to investigate the effects of non-structural components (NSCs) and lignin removal on alkaline extraction of hemicellulose. Although NSCs were found to have a minimal effect on hemicellulose dissolution, they affected the color values of the hemicellulose extracts. The lignin limited the hemicellulose dissolution and increased the color value by binding to hemicellulose molecules and forming lignin-carbohydrate complexes. Sodium chlorite method can remove about 90% lignin from corn stover, especially the lignin connected to hemicellulose through p-coumaric and ferulic acids. Which increased the hemicellulose dissolution ratio to 93% and reduced the color value 14-28%, but the cost is about 20% carbohydrates lost.

Endoscopic transforaminal thoracic foraminotomy and discectomy for the treatment of thoracic disc herniation.

Thoracic disc herniation is a relatively rare yet challenging-to-diagnose condition. Currently there is no universally accepted optimal surgical treatment for symptomatic thoracic disc herniation. Previously reported surgical approaches are often associated with high complication rates. Here we describe our minimally invasive technique of removing thoracic disc herniation, and report the primary results of a series of cases. Between January 2009 and March 2012, 13 patients with symptomatic thoracic disc herniation were treated with endoscopic thoracic foraminotomy and discectomy under local anesthesia. A bone shaver was used to undercut the facet and rib head for foraminotomy. Discectomy was achieved by using grasper, radiofrequency, and the Holmium-YAG laser. We analyzed the clinical outcomes of the patients using the visual analogue scale (VAS), MacNab classification, and Oswestry disability index (ODI). At the final follow up (mean: 17 months; range: 6-41 months), patient self-reported satisfactory rate was 76.9%. The mean VAS for mid back pain was improved from 9.1 to 4.2, and the mean ODI was improved from 61.0 to 43.8. One complication of postoperative spinal headache occurred during the surgery and the patient was successfully treated with epidural blood patch. No other complications were observed or reported during and after the surgery.

A simple technique of accessing the L5-S1 disc space for transforaminal endoscopic spine surgery.

Transforaminal endoscopic spine surgery is increasingly used to treat a range of spinal conditions. The success of the surgery requires an accurate insertion of the guide needle and a precise placement of the working cannula and endoscope. However, such a precise placement is challenging for many surgeons to achieve when the pathology is located at the L5-S1 level. On the basis of our years of experience with performing transforaminal endoscopic spine surgery, we have developed a simple technique to help surgeons safely access the L5-S1 level. The technique has been proven intuitive and easy for experienced as well as inexperienced surgeons to learn. The key steps of the technique involve identifying an appropriate entry point on the skin and choosing an accurate trajectory angle for insertion. The purpose of this chapter is to report how to easily identify the entry point and choose a trajectory angle depending on the patient's anatomic characteristics.

Endoscopic anterior cervical discectomy under epidurogram guidance.

Cervical discectomy is commonly required for spinal cord and nerve compression disorders. Currently, anterior cervical discectomy and fusion is the standard procedure for the treatment of cervical disc herniations and cervical degenerative disorders, whereas endoscopic cervical discectomy is considered an important alternative. Despite the advancement in surgical technology, endoscopically removing hard pathological tissues remains challenging. Inspired by lumbar epidurogram-guided decompression, we have developed an epidurogram-guided endoscopic cervical decompression technique. The technique uses contrast dye through cervical discography to generate an epidurogram. Under fluoroscopic view, the spinal cord is posterior to the contrast line. The endoscopic instruments can safely reach the epidural space, if it's necessary, as long as they stay anterior to the contrast line. We have used this technique to treat both soft and hard cervical disc herniations, and we have found it makes the surgical procedures safer when more aggressive decompression is required.

Transforaminal endoscopic lumbar procedure for disc herniations: a "between" technique.

Despite the advancement of surgical techniques in endoscopic spine surgeries, treatment of central and paracentral disc herniations, especially disc extrusions and disc sequestrations, remains challenging. On the basis of our experience with treating disc tears, disc herniations, and other spinal diseases, we have developed a new technique we call the "between" technique. This technique involves positioning the opening of the endoscope access cannula at the edge of the targeted disc with half of the opening being positioned inside the disc and the other half positioned in the epidural space. The "between" technique uses a blunt-ended dilator as a navigating tool in the epidural space to find the ideal access path and initial location for the access cannula. The technique is safe, effective, and easy to use. It has been proven particularly efficacious for the treatment of central and paracentral extruded disc herniations and sequestered disc herniations. The purpose of this Chapter is to describe this technique and introduce its application in removing central and paracentral disc extrusions and sequestrations.